Pyridine non-classical cannabinoid compounds and related methods of use

ABSTRACT

Disclosed are compounds of the formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , V, W, X, Y and Z can be as defined herein. The compounds can be used in the treatment of disorders mediated by the cannabinoid receptors.

This application is a divisional of and claims priority benefit fromco-pending application Ser. No. 12/468,776 filed May 19, 2009, nowissued as U.S. Pat. No. 8,158,654, which claims priority benefit fromapplication Ser. No. 61/128,088 filed May 19, 2008, incorporated hereinby reference in its entirety.

BACKGROUND OF THE INVENTION

The classical cannabinoid, delta-9-tetrahydrocannabinol (Δ⁹-THC), is themajor active constituent extracted from Cannabis sativa. The effects ofcannabinoids are due to an interaction with specific high-affinityreceptors. Presently, two cannabinoid receptors have been characterized:CB-1, a central receptor found in the mammalian brain and a number ofother sites in the peripheral tissues; and CB-2, a peripheral receptorfound principally in cells related to the immune system. In addition, ithas recently been reported that the GPR35 and GPR55 orphan receptorsbind cannabinoid type ligands and have been proposed as a third receptorsubtype. The CB-1 receptor is believed to mediate the psychoactiveproperties associated with classical cannabinoids. Characterization ofthese receptors has been made possible by the development of specificsynthetic ligands such as the agonists WIN 55212-2 (D'Ambra et al., J.Med. Chem. 35:124 (1992)) and CP 55,940 (Melvin et al., Med. Chem. 27:67(1984)).

Pharmacologically, cannabinoids can be used to affect a variety oftargets such as the central nervous system, the cardiovascular system,the immune system and/or endocrine system. More particularly, compoundspossessing an affinity for either the CB-1 or the CB-2 receptors andpotentially the GPR35 and GPR55 receptors are useful as anticanceragents, antiobesity agents, analgesics, myorelaxation agents andantiglaucoma agents. Such compounds can also be used for the treatmentof thymic disorders, vomiting; various types of neuropathy, memorydisorders, dyskinesia, migraine, multiple sclerosis; asthma, epilepsy,ischemia, angor, orthostatic hypotension, osteoporosis, liver fibrosis,inflammation and irritable bowel disease, and cardiac insufficiency.

However, certain cannabinoids such as Δ⁹-THC also affect cellularmembranes, producing undesirable side effects such as drowsiness,impairment of monoamine oxidase function, and impairment of non-receptormediated brain function. The addictive and psychotropic properties ofsome cannabinoids tend to limit their therapeutic value.

A number of structurally distinct non-classical bi- and triarylcannabinoids are described in U.S. Pat. No. 7,057,076 to Makriyannis etal. Makriyannis identifies a range of binding affinities for two or morecompounds, but does not provide any supporting data that shows thebinding data of individual compounds on both the CB-1 and CB-2receptors. It is difficult to assess, therefore, whether any of thecompounds are selective for one receptor over another.

There still remains an ongoing need in the art for compounds, whetherclassical or non-classical cannabinoid analogs, that can be used fortherapeutic purposes to affect treatment of conditions or disorders thatare mediated by the CB-1 receptor and/or the CB-2 receptor.

SUMMARY OF THE INVENTION

In light of the foregoing, it is an object of the present invention toprovide a range of heterocyclic cannabinoid analog compounds,compositions and/or related methods, thereby overcoming variousdeficiencies and shortcomings of the prior art, including those outlinedabove. It will be understood by those skilled in the art that one ormore aspects of this invention can meet certain objectives, while one ormore other aspects can meet certain other objectives. Each objective maynot apply equally, in all its respects, to every aspect of thisinvention. As such, the following objects can be viewed in thealternative with respect to any one aspect of this invention.

It can be an object of the present invention to identify one or moreclasses of cannabinoid compounds exhibiting affinity for cannabinoid andrelated receptors found in human cells and tissues.

It is also an object of the present invention to provide one or morepyridine non-classical cannabinoid receptor ligands comprising a B-ringpyridine system, such compounds can comprise bi- or triaryl ring system.

It can be another object of the present invention to identify suchcompounds exhibiting cannabinoid receptor selectivity for directedtherapeutic use.

Other objects, features, benefits and advantages of the presentinvention will be apparent from this summary and the followingdescriptions of certain embodiments, and will be readily apparent tothose skilled in the art having knowledge of various cannabinoidcompounds and related therapeutic methods. Such objects, features,benefits and advantages will be apparent from the above as taken intoconjunction with the accompanying examples, data, figures and allreasonable inferences to be drawn therefrom, alone or with considerationof the references incorporated herein.

In part, the present invention can be directed to a cannabinoid analogcompound selected from compounds of a formula (I) below

wherein one of W and V can be N and the other can be C; X can beselected from H, substituted and unsubstituted alkyl, and cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, wherein each alkyl portioncan be optionally substituted up to three times and the ring portion ofeach can be optionally substituted with one, two, three, four or fivesubstituents; Y can be selected from S, O, CH₂, CH(CH₃), CH(OH),C(CH₃)(OH), C(CH₃)₂, C(—U(CH₂)_(n)U—), C(O), NH, S(O), and S(O)₂; n canbe an integer ≧1, and preferably from 1 to 6; U can be selected fromCH₂, S, and O; Z can be selected from H, substituted and unsubstitutedalkyl, and cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereineach alkyl portion can be optionally substituted up to three times andthe ring portion of each can be optionally substituted with one, two,three, four or five substituents; and R₁ and R₂ are independentlyselected from H and substituted and unsubstituted alkyl.

In part, the present invention can be directed to a salt of a compoundin accordance herewith.

In part, the present invention can be directed to a pro-drug of acompound in accordance herewith.

In part, the present invention can also be directed to a pharmaceuticalcomposition comprising a compound of the sort described herein, a saltand/or a pro-drug thereof; and a pharmaceutically acceptable carriercomponent.

In part, the present invention can be directed to a method of modifyingthe activity of a cannabinoid receptor. Such a method can compriseproviding a compound, salt and/or pro-drug of the present invention orany other compound disclosed herein that has activity at a cannabinoidor related receptor, a salt and/or pro-drug thereof; and contacting acell and/or cannabinoid receptor of a cell with such a compound. Asillustrated below, such contact can be at least partially sufficient toat least partially modify activity of such a cannabinoid receptor.

In part, the present invention can also be directed to a method oftreating a cannabinoid receptor-mediated condition. Such a method cancomprise providing a compound in accordance herewith or any othercompound disclosed herein that has activity at a cannabinoid receptor, asalt and/or pro-drug thereof; and administering to a patient an amountof such a compound, salt and/or pro-drug, that can be at least partiallyeffective to treat a cannabinoid receptor-mediated condition. Thisaspect of the invention can relate to the use of agonists of a CB-1 or arelated receptor, antagonists of a CB-1 or related receptor, agonists ofa CB-2 or related receptor, and/or antagonists of a CB-2 or relatedreceptor to treat or prevent disease conditions mediated byhyperactivity of CB-1 and/or CB-2 (or related) receptors or eitherinactivity or hypoactivity of the CB-1 and/or CB-2 (or related)receptors.

In part, the present invention can also be directed to a compoundselected from compounds of a formula

wherein one of W and V can be N and the other can be C; X can be alkylor can be selected from phenyl, benzyl, cyclohexyl, thiophenyl andpyridinyl, the ring portion of each can be optionally substituted withone to five substituents independently selected from halo, alkyl andalkoxy moieties; R₁ and R₂ can be independently selected from H oralkyl; Y can be selected from carbonyl, dimethylmethylene andhydroxymethylene; and Z can be alkyl or can be selected from cycloalkyl,phenyl and thiophenyl, each of which can be optionally substituted withone to five substituents as would be understood by those skilled in theart made aware of this invention, including but not limited to thosedescribed elsewhere herein. In certain embodiments, X can be selectedfrom phenyl optionally substituted with from one to five groupsindependently selected from chloro, methyl and methoxy substituents. Incertain such embodiments, Z can be an alkyl or a phenyl moiety and,optionally, X can be a benzyl or dichlorophenyl moiety. Regardless, sucha compound can be selected from salts and/or pro-drugs of such acompound.

Without limitation, this invention can also be directed to a method ofcancer treatment. Such a method can comprise providing a cancer cellcomprising a cannabinoid receptor, such a cell of a growth of cancercells; and contacting such a growth with a cannabinoid compound selectedfrom compounds of a formula

wherein R₂, V, W, X, Y and Z can be as defined above. In an embodiment,X can be alkyl or can be selected from phenyl, cyclohexyl, thiophenyland pyridinyl, each of which can be optionally substituted with one tofive substituents independently selected from halo, alkyl and alkoxymoieties; R₁ and R₂ can be independently selected from H or alkyl; Y canbe selected from carbonyl, dimethylmethylene and hydroxymethylene; and Zcan be alkyl or can be selected from cyclohexyl, phenyl and thiophenyl,each of which can be optionally substituted with one to fivesubstituents as would be understood by those skilled in the art madeaware of this invention, including but not limited to those describedelsewhere herein; and salts and pro-drugs of said compounds andcombinations thereof, such compound(s) in an amount at least partiallysufficient to induce death of a cell of such a growth. In certainembodiments, X and Z can be phenyl optionally substituted with from oneto five groups independently selected from chloro, hydroxy and methoxy.In certain such embodiments, R₁ and R₂ can be independently selectedfrom H and methyl moieties. In certain such embodiments, at least one ofR₁ and R₂ can be a moiety other than methyl. Regardless, withoutlimitation and as illustrated elsewhere herein, Y can be carbonyl ordimethylmethylene.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the functional activity of compound 5e at the CB-1receptor.

FIG. 2 shows the functional activity of compound 5e at the CB-2receptor.

FIG. 3 shows the secretion profiles of G-CSF by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-α at4 and 18 hour intervals.

FIG. 4 shows the secretion profiles of IL-1β by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-α at4 and 18 hour intervals.

FIG. 5 shows the secretion profiles of IL-6 by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-αscaled to show the levels at the 18 hour interval.

FIG. 6 shows the secretion profiles of IL-6 by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-αscaled to show the levels at the 4 hour interval.

FIG. 7 shows the secretion profiles of IL-8 by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-αscaled to show the levels at the 18 hour interval.

FIG. 8 shows the secretion profiles of IL-8 by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-αscaled to show the levels at the 4 hour interval.

FIG. 9 shows the secretion profiles of MCP-1 by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-α at4 and 18 hour intervals.

FIG. 10 shows the secretion profiles of MIF by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-αscaled to show the levels at the 4 hour interval.

FIG. 11 shows the secretion profiles of MIF by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-αscaled to show the levels at the 18 hour interval.

FIG. 12 shows the secretion profiles of RANTES by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-αscaled to show the levels at the 18 hour interval.

FIG. 13 shows the secretion profiles of RANTES by A549 cells exposed tocompound 5b at the EC1 and EC10 in the presence and absence of TNF-αscaled to show the levels at the 4 hour interval.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The novel compounds encompassed by the instant invention are thosedescribed by the general formula I set forth above, and the salts,pro-drugs and/or pharmaceutical compositions thereof.

By “alkyl” in the present invention is meant straight or branched chainalkyl radicals having from 1-20 carbon atoms. Optionally, an alkyl groupof the instant invention can contain one or more double bonds and/or oneor more triple bonds.

By “cycloalkyl” is meant a carbocyclic radical having from three totwelve carbon atoms. The cycloalkyl can be monocyclic or a polycyclicfused system. Optionally, a cycloalkyl group of the instant inventioncan contain one or more double bonds and/or one or more triple bonds.

The term “heterocyclyl” refers to one or more carbocyclic ring systemsof 4-, 5-, 6- or 7-membered rings which includes fused ring systems andcontains at least one and up to four heteratoms selected from nitrogen,oxygen or sulfur and combinations thereof.

By “aryl” is meant an aromatic carbocyclic ring system having a singlering, multiple rings or multiple condensed rings in which at least onering is aromatic.

The term “heteroaryl” refers to one or more aromatic ring systems havingfrom three to twelve atoms which includes fused ring systems andcontains at least one and up to four heteroatoms selected from nitrogen,oxygen or sulfur and combinations thereof.

By “arylalkyl” is meant an alkyl radical substituted with an aryl, withthe the point of attachment is a carbon of the alkyl chain.

As used herein, “substituted” refers to those substituents as would beunderstood by those skilled in the art. At least one and as many as fivesubstituents can exist on a single group. Examples of such substituentsinclude, but are not limited to, halo, alkyl, alkoxy, hydroxyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, cyano, nitro, amino,alkylamino, dialkylamino, thiol, alkylthiol, haloalkyl (e.g.trifluoromethyl), carboxy, alkylcarboxy, carbamoyl and the like.

According to one approach, representative, non-limiting pyridinepyrimidine analogs can be prepared by reacting an intermediate compoundaccording to the retro-synthetic equation shown below in Scheme 1.

In Scheme 1, R₃ and R₄ are selected from methyl, ethyl, andtrichlorophenyl. Compounds related to II are readily prepared from theappropriate dialkyl or diaryl malonate via standard procedures includingdirect alkylation of the malonate using a base such as sodium ethoxideor a copper catalyzed coupling as depicted in Scheme 2 and described byYip, et al. See, Org. Lett 9:3469, the entirety of which is incorporatedherein by reference.

Intermediate III is readily prepared from aromatic and aliphaticnitriles using established chemistry including methyl magnesiumbromide/THF or methyl lithium followed by hydrolysis of the intermediateenamine (See, e.g., Moss, Tet. Lett. 36:8761, the entirety of which isincorporated herein by reference) (Scheme 3). Intermediate IV is readilyprepared from the corresponding nitrile and methyl lithium utilizingstandard procedures.

Derivatives containing a gem-dialkyl, heterocyclic, or carbocyclicsubstituent at Y, where commercial compounds are not available, areprepared either by direct alkylation of the methylene nitrile (See U.S.Pat. No. 7,057,76 to Makriyannis and Pub. No. 2004/087590, each of whichis incorporated herein by reference in its entirety) or from theappropriately substituted aryl, heteroaryl halogen and isopropyl nitrile(See U.S. Pub. No. 2005/0065033 filed Aug. 21, 2003, the entirety ofwhich is incorporated herein by reference.). Schemes 4 and 5 arerepresentative of but not limited to the scope of this chemistry.

Derivatives containing a keto, hydroxyl, alkylhydroxyl substituent at Ycan be prepared by direct oxidation of compounds bearing a Y═CH₂ or fromthe C2-aldehyde pyridine, prepared from2,2-bis-ethylsulfanyl-acetamidine and the appropriately substitutedmalonic acid ester (Scheme 6) using chemistry previously reported (SeeU.S. Pat. No. 7,169,942, the entirety of which is incorporated herein byreference).

The corresponding pyridines are prepared by reacting dimethyl-,diethyl-, or bis(trichlorophenyl)-malonates with the appropriatelysubstituted Schiff base derived from the requisite 2-keto analogs, asdepicted in Scheme 7 (Ito and Miyajima, J. Heterocyclic Chem. 1992,29:1037, and Kappe et al., J. Heterocyclic Chem 1988, 25:463, each ofwhich is incorporated herein by reference in its entirety), wherein R₂is benzyl or t-butyl and R₃, R₄ are methyl, ethyl, phenyl, and/orbis(trichlorophenyl. Alternatively, the requisite imine is prepared fromthe appropriate nitrile and methyl lithium using standard procedures.

While syntheses of several representative, non-limiting compounds aredescribed herein, it will be understood by those skilled in the art thatvarious other compounds can be prepared using similar such proceduresand/or straight-forward modifications thereof. Accordingly, theidentities of moieties X, R₁, R₂, Y and Z are limited only by therespective reagents, starting materials, intermediates and chemistrythereon. Various other such moieties and/or substituents thereof includebut are not limited to those described in the aforementioned co-pendingapplication.

Likewise, the present invention contemplates, more broadly, variousother such compounds, salts and/or pro-drugs thereof, together withcorresponding pharmaceutical compositions thereof, as also described inthe aforementioned co-pending application. Such compounds, salts,pro-drugs and/or pharmaceutical compositions can be used as describedtherein. For instance, the present invention can be used to modify theactivity of one or both of the CB-1 and CB-2 receptors. Such a methodcan be carried out by contacting a cell and/or cannabinoid receptorthereof with a compound of the present invention, such contact at leastpartially sufficient to at least partially modify the activity of such acannabinoid receptor, whether ex vivo or in vivo.

More generally, various physiological and/or therapeutic advantages ofthe present compounds and/or compositions can be realized withconsideration of the authorities cited in the aforementioned co-pendingapplication. The inventive analogs, as described herein, can beadministered in therapeutically-effective amounts to treat a wide rangeof indications. Without limitation, various such conditions and/ordisease states are described in paragraph 0067 of co-pending applicationSer. No. 12/074,342, filed Mar. 3, 2008 and entitled“Tri-Aryl/Heteroaromatic Cannabinoids and Use Thereof,” the entirety ofwhich is incorporated herein by reference.

Accordingly, this invention can be directed to a method comprisingproviding a compound of the sort described herein, such a compoundexhibiting activity at a cannabinoid receptor; and contacting a cellcomprising a cannabinoid receptor with such a compound and/oradministering such a compound to a patient, such a compound in an amountat least partially effective to treat a cannabinoid receptor/mediatedcondition. Such a cannabinoid receptor can be a receptor describedherein or as would otherwise be understood or realized by those skilledin the art made aware of this invention.

The activity of cannabinoid and related receptors can be affected,mediated and/or modified by contacting such a receptor with an effectiveamount of one or more of the present compounds as can be present in oras part of a pharmaceutical composition or treatment, or by contacting acell comprising such a receptor with an effective amount of one or moresuch compounds, so as to contact such a receptor in the cell therewith.Contacting may be in vitro or in vivo. Accordingly, as would beunderstood by those skilled in the art, “contact” means that acannabinoid and/or related receptor and one or more compounds arebrought together for such a compound to bind to or otherwise affect ormodify receptor activity. Amounts of one or more such compoundseffective to modify and/or affect receptor activity can be determinedempirically and making such a determination is within the skill in theart.

Without limitation, analog compounds of this invention can be used exvivo in receptor binding assays of the sort described in Example 2 ofthe aforementioned co-pending '342 application. In vitro activity of thepresent analog compounds can be demonstrated in a manner similar to thatdescribed in Example 3 of the co-pending application. Alternatively, invivo activity can be demonstrated using the protocols described inExamples 4 and 6, thereof More specifically, anti-cancer activity ofvarious representative compounds of this invention can be shown againsthuman lung, prostate, colorectal and pancreatic cancer cell lines usingthe methodologies described in Example 9 of the aforementionedco-pending '342 application. Extending such a methodology, the presentinvention can also be used to treat cancer growth of the central nervoussystem and/or induce cellular death within such growth. In accordancewith this invention, various cannabinoid compounds of the sort describedherein, including but not limited to those discussed above, can also beused in conjunction with a method to treat human glaucoma and/or braincancers. Illustrating such embodiments, one or more compounds of thepresent invention can be provided and used, as described in theco-pending application, to contact and/or treat human brain cancers,such contact and/or treatment as can be confirmed by cell death and/orrelated effects.

EXAMPLES OF THE INVENTION

The following non-limiting examples and data illustrate various aspectsand features relating to the compounds, compositions and/or methods ofthe present invention, including the synthesis of pyridine non-classicalcannabinoid receptor ligands and/or compounds, as are available thoughthe methodologies described herein. In comparison with the prior art,the present compounds and methods provide results and data which aresurprising, unexpected and contrary thereto. While the utility of thisinvention is illustrated through the preparation and use of severalcompounds, moieties and/or substituents thereof, it will be understoodby those skilled in the art that comparable results are obtainable withvarious other compounds, moieties and/or substituents, as arecommensurate with the scope of this invention. All compounds are namedusing ChemBioDraw Ultra Version 11.0.01.

Example 1a

Diethyl 2-phenylmalonate—A two-necked round-bottomed flask was chargedsequentially with CuI (0.114 g, 0.6 mmol), 2-picolinic acid (0.148 g,1.2 mmol), CsCO₃ (5.89 g, 18 mmol), and aryl iodide (6 mmol), if asolid. The vial was evacuated and back filled with nitrogen 3 times.Anhydrous 1,4-dioxane (10 ml) was added volumetrically followed bydistilled malonate (1.9 ml, 12 mmol) and phenyl iodide (12 mmol). Thevial was sealed and heated to 70° C. After monitoring the progress byTLC, the reaction was cooled to room temperature, separated with ethylacetate and washed with ammonium chloride. The organic phase was driedover sodium sulfate, and purified by column chromatography using 10%EtOAc/Hexane mixture. Yield: 92%, R_(f)=0.41 (ethyl acetate/hexane=1:9).¹H NMR (CDCl₃,500 MHz: δ7.41-7.31, m, 5H), 4.62 (s, 1H),4.25-4.15 (m,4H), 1.26 (t, 6H). MS 259 (M+23).

Example 1b

In a similar fashion the following malonic acid esters were synthesized.

Diethyl 2-m-tolylmalonate—Yield: 92%, R_(f)=0.55 (ethylacetate/hexane=1:9). ¹H NMR (CDCl₃, 500 MHz: δ δ7.12-7.3 (m, 4H), 4.62(s, 1H), 4.20-4.28 (m, 4H), 2.27 (s, 3H), 1.22-1.25 (m, 6H). MS 273(M+23).

Example 1c

Diethyl 2-(pyridin-2-yl)malonate—Yield: 88%, R_(f)=0.29 (ethylacetate/hexane=3:7). ¹H NMR (CDCl₃, 500 MHz: δ 8.5 (d, 1H), 7.7 (d, 1H),7.62-7.58 (m, 1H), 7.18-7.12 (m, 1H), 4.80 (s, 1H), 4.21-4.15 (m, 4H),1.21 (t, 6H). MS 260 (M+23).

Example 1d

Diethyl 2-(thiophen-2-yl)malonate—Yield: 63%, R_(f)=0.29 (ethylacetate/hexane=1:9). ¹H NMR (CDCl₃, 300 MHz: δ 7.28 (d, 1H), 7.1-7.0 (m,2H), 4.8 (s, 1H), 4.26-4.2 (m, 4H), 1.2 (t, 6H). MS 265 (M+23).

Example 1e

Diethyl 2-cyclohexylmalonate—Yield: 94%, R_(f)=0.59 (ethylacetate/hexane=1:9). ¹H NMR (CDCl₃, 500 MHz: δ 4.22-4.14 (m, 4H), 3.12(d, 1H), 2.14-2.05 (m, 1H), 1.75-1.63 (m, 5H), 1.34-1.24 (m, 8H),1.20-1.20 (m, 3H). MS 265 (M+23).

Example 1f

Diethyl 2-hexylmalonate—Yield: 91%, R_(f)=0.44 (ethylacetate/hexane=1:9). ¹H NMR (CDCl₃, 300 MHz: δ 4.11-4.40 (m, 4H), 331(t, 1H), 1.80 (m, 2H), 1.38 (m, 2H), 1.1-1.4 (m, 12H), 0.8 (t, 3H). MS267 (M+23).

Example 1g

Diethyl 2-(3-methoxyphenyl)malonate—Product identified by MS 289 (M+23).

Example 1h

Diethyl 2-(3,5-dichlorophenyl)malonate—Product identified by MS 328(M+23).

Example 1i

Diethyl 2-(2,4-dichlorophenyl)malonate—Product identified by: MS 328(M+23).

Example 1j

Diethyl 2-(4-(trifluoromethyl)phenyl)malonate—Product identified by MS327 (M+23).

Example 1k

Diethyl 2-(pyrazin-2-yl)malonate—Product identified by MS 261 (M+23).

Example 1l

Diethyl 2-(pyrimidin-2-yl)malonate—Product identified by MS 261 (M+23).

Example 1m

Diethyl 2-(naphthalen-1-yl)malonate—Product identified by MS 309 (M+23).

Example 1n

Diethyl 2-(1H-pyrrol-3-yl)malonate—Product identified by MS 249 (M+23).

Example 1o

Diethyl 2-cyclopentylmalonate—Product identified by MS 251 (M+23).

Example 2a

2-Methyl-2-(thiophen-2-yl)propanenitrile—To a solution of2-(thiophen-2-yl) acetonitrile (1 g, 8.13 mmol) in 4 ml anhydrous THF,KHMDS (24.4 mmol, 48.9 ml, 0.5M in toluene) was added at 0° C. Themixture was allowed to stir for 3 minutes, after which a solution of16.26 mmol iodomethane (1.13 ml in 26 ml anhydrous THF) was added slowlyover a period of 10 minutes. The mixture was stirred for 5 minutes andmonitored by TLC. Upon completion, the reaction was quenched withaqueous ammonium chloride. The organic phase was separated with ethylacetate and dried over sodium sulfate. The product was purified viavacuum distillation (bp 42° C. at 1 torr) Yield: 89%. ¹H NMR (500 MHz,CDCl₃): δ (ppm) 7.4 ppm (d, 1H), 7.2 ppm (t, 1H), 7.0 ppm (d, 1H), 1.9ppm (s, 6H).

Example 2b

In a similar fashion the following compound was synthesized.

2,2-Dimethyloctanenitrile—Purified via vacuum distillation (Bp 50-55° C.at 1.1 torr). Yield: 84% I.R. (neat) nitrile 2230 cm⁻¹, ¹H NMR (500 MHz,CDCl₃): δ (ppm) 1.5 ppm (m, 4H). 1.4-1.3 ppm (m, 12H), 0.9 ppm (s, 3H).

Example 3a

2-Methyl-2-phenylpropanenitrile—To a solution of fluorobenzene (5.85 mL,62 4 mmol) in 100 mL of anhydrous toluene was added isobutyronitrile(22.5 mL, 250 mmol) followed by 200 mL (100 mmol) of a 0.5 M solution ofKHMDS in toluene. The reaction was stirred at 80° C. for 24 hours. Thereaction was then allowed to cool to room temperature, diluted withdiethyl ether, and washed with water and brine. The organic fraction wasthen dried over sodium sulfate and concentrated under reduced pressure.The product was purified by flash chromatography using an ethylacetate/hexanes gradient to yield 4.57 g (50%) of the objective compoundas a brown oil. MS: (ESI, Pos) m/z 168.0 (M+23) ¹H NMR (500 MHz, CDCl₃):δ (ppm) 7.48 (d, 2H), 7.39 (t, 2H), 7.31 (t, 1H), 1.73 (s, 6H).

Example 3b

In a similar fashion the following compounds were synthesized.

2-Methyl-2-pyridin-2-yl-propanenitrile—Purified in a manner similar to2-methyl-2-phenylpropanenitrile using 2-bromopyridine as the startingmaterial to yield a brown oil. MS: (ESI, Pos) m/z 168.9 (M+23).

Example 3c

2-Cyclohexyl-2-methylpropionitrile—Colorless oil, Yield:89% MS: (ESI,Pos.) 174.0 (M+1) ¹HNMR (500 MHz, CDCl₃): ∂(ppm) 1.81-1.89(m, 4H),1.7(m, 1H), 1.19-1.34(m, 7H), 1.07-1.28(m, 5H).

Example 4a

3-Methyl-3-phenylbutan-2-one—To a solution of2-methyl-2-phenyl-propionitrile (3a, 500 mg, 3.1 mmol) in anhydrous THFcooled to 0° C. was added methyl magnesium bromide (408 mg, 3.4 mmol).The reaction was warmed to room temperature and then refluxed overnight.The mixture was treated with 1N HCl and the aqueous phase extracted withdiethyl ether. Product was confirmed by MS: (ESI, Pos) m/z 187.2 (M+23).

Example 4b

Various other ketones can be prepared from the respective nitriles usingsynthetic procedures comparable to those described above to provide thecorresponding Schiffs base compounds en route to the Y- and/orZ-substituted pyridine intermediates, as illustrated herein.

Example 5a

6-(2-(Thiophen-2-yl)propan-2-yl)-3-m-tolylpyridine-2,4-diol (5a)—To asolution of 2a (0.83 g,5.5 mmol) in anhydrous diethyl ether(5 mL) wasadded under argon 1.6M methyl lithium in diethyl ether (21 mL, 33.00mmol) and the mixture was stirred for 3hrs. at room temperature. Afterquenching with water, the mixture was extracted with diethyl ether. Theextracts were dried over anhydrous Na₂SO₄ and the solvent was evaporatedunder reduced pressure to afford a colorless oil (0.86, 95%). A solutionof the intermediate product (3-methyl-3-(thiophen-2-yl)butan-2-imine;0.73g, 4.36 mmol) and diethyl 2-m-tolylmalonate (0.70 g,4.36 mmol) in 1mL diglyme was refluxed at 135° C. for 3 hours. The reaction mixture wascooled and poured into hexane to afford a yellow precipitate, which wascollected and crystallized from ethyl acetate/hexane mixture. Off whitepowder, Yield: 52% MS: (ESI, Neg) 323.90 (M−1) ¹HNMR (500 MHz, DMSO-d6):∂(ppm) 10.69(s, 1H), 10.19(s, 1H), 7.46(d, 1H), 7.11-7.19(m, 3H),6.99-7.05(m, 3H), 5.78(s, 1H), 2.28(s, 3H), 1.72(s, 6H).

Example 5b

In a similar manner the following compounds were prepared.

6-(2-Cyclohexylpropan-2-yl)-3-(3,5-dichlorophenyl)pyridine-2,4-diol(5b)—White powder, Yield: 40% MS: (ESI, Neg) 377.9 (M−1) ¹HNMR (300 MHz,DMSO-d6): ∂(ppm) 10.88(s, 1H), 10.71(s, 1H), 7.51(m, 3H), 5.90(s, 1H),2.29(s, 3H), 1.4-1.9(m,7H), 1.11-1.14(m,10H).

Example 5c

3-(3,5-Dichlorophenyl)-6-(2-phenylpropan-2-yl)pyridine-2,4-diol(5c)—White powder, Yield: 63% MS: (ESI, Neg) 372.7 (M−1) ¹HNMR (500 MHz,DMSO-d6): ∂(ppm) 10.79(s, 1H), 10.74(s, 1H), 7.26-7.49(m, 8H), 5.96(s,1H), 1.63(s, 6H).

Example 5d

3-(3,5-Dichlorophenyl)-6-(2-(thiophen-2-yl)propan-2-yl)pyridine-2,4-diol(5d)—Off white powder, Yield: 47% MS: (ESI, Neg) 377.9 (M−1) ¹HNMR (500MHz, DMSO-d6): ∂(ppm) 10.95(s, 1H), 10.77(s, 1H), 7.46-7.48(m, 3H),7.41(t, 1H), 7.01-7.05(m, 2H), 5.78(s, 1H), 1.72(s, 6H).

Example 5e

3-(3,5-dichlorophenyl)-6-(2-methyloctan-2-yl)pyridine-2,4-diol(5e)—White powder, Yield: 47% MS: (ESI, Neg) 379.9 (M−1) ¹HNMR (500 MHz,DMSO-d6): ∂(ppm) 10.96(s, 1H), 10.72(s, 1H), 7.51(d, 2H), 7.40(t, 1H),5.94(s, 1H), 1.60-1.63(m, 2H), 1.04-1.24(m, 14H), 0.84(t, 3H).

Example 5f

6-(2-Cyclohexylpropan-2-yl)-3-m-tolylpyridine-2,4-diol (5f)—Whitepowder, Yield: 48% MS: (ESI, Neg) 324.0 (M−1) ¹HNMR (300 MHz, DMSO-d6):∂(ppm) 10.81(s, 1H), 10.25(s, 1H), 7.17-7.19(m, 4H), 5.91(s, 1H),2.29(s, 3H), 1.4-1.9(m, 7H), 1.11-1.14(m, 10H).

Example 5g

6-(2-Phenylpropan-2-yl)-3-m-tolylpyridine-2,4-diol (5g)—White powder,Yield: 61% MS: (ESI, Neg) 317.9 (M−1) ¹HNMR (300 MHz, DMSO-d6): ∂(ppm)10.51(s, 1H), 10.23(s, 1H), 6.99(m, 9H), 5.93(s, 1H), 2.28(s, 3H),1.62(s, 6H).

Example 5h

6-(2-Methyloctan-2-yl)-3-(m-tolyl)pyridine-2,4-diol (5h)—White powder,Yield: 41% MS: (ESI, Neg) 326.1 (M−1) ¹HNMR (500 MHz, CDCl₃): ∂(ppm)7.34 (t, 1H) 7.19-7.26(m, 3H), 5.94(s, 1H), 2.39(s, 3H), 1.56(m, 2H),1.16-1.30(m, 14H), 0.88(t, 3H).

Example 5i

3-Hexyl-6-(2-methyloctan-2-yl)pyridine-2,4-diol (5i)—White powder,Yield:38% MS: (ESI, Neg) 320.0 (M−1) ¹HNMR (300 MHz, CDCl₃): ∂(ppm)5.89(s, 1H), 2.71(m, 2H), 1.61-1.58(m, 2H), 1.25-1.42(m, 22H), 0.98(m,6H).

Example 5j

6-(2-Methyloctan-2-yl)-3-phenylpyridine-2,4-diol (5j)—White powder,Yield: 38% MS: (ESI, Neg) 312.1 (M−1) ¹HNMR (500 MHz, CDCl₃): ∂(ppm)7.42-7.49(m, 4H), 7.35-7.38(m, 1H), 5.93(s, 1H), 1.53-1.56(m, 2H),1.14-1.27(m, 14H), 0.87(t, 3H).

Example 5k

3-Cyclohexyl-6-(2-methyloctan-2-yl)pyridine-2,4-diol (5k)—White powder,Yield:39% MS: (ESI, Neg) 318.0 (M−1) ¹HNMR (300 MHz, MeOD): ∂(ppm)5.90(s, 1H), 2.81(m, 1H), 2.10(m, 2H), 1.61-1.58(m, 6H), 1.18-1.43(m,18H), 0.88(t, 3H).

Example 5l

6′-(2-Methyloctan-2-yl)-2,3′-bipyridine-2′,4′-diol (5l)—Pale yellowpowder, Yield: 23% MS: (ESI, Neg) 313.1 (M−1) ¹HNMR (300 MHz, CDCl₃):∂(ppm) 9.28-9.31(d, 1H), 8.9 (s, 1H), 8.31(d, 1H),7.89-7.91(t,1H),7.22-7.27(t, 1H), 5.95(s, 1H), 1.58-1.62(m, 2H), 1.22-1.31(m, 14H),0.86(t, 3H).

Example 5m

3-(3-Methoxyphenyl)-6-(2-methyloctan-2-yl)pyridine-2,4-diol (5m)—Whitepowder, Yield: 45% MS: (ESI, Neg) 342.0 (M−1) ¹HNMR (300 MHz, DMSO-d6):∂(ppm) 10.78(s, 1H), 10.19(s, 1H), 7.21(m, 1H), 6.95-6.96(m, 2H),6.73-6.81(m, 1H), 5.85(s, 1H), 3.7(s, 3H), 1.59-1.67(m, 2H),1.04-1.22(m, 14H), 0.84(t, 3H).

Example 5n

3-Benzyl-6-(2-methyloctan-2-yl)pyridine-2,4-diol (5n)—White powder,Yield: 41% MS: (ESI, Neg) 326.0 (M−1) ¹HNMR (300 MHz, CDCl₃): ∂(ppm)7.24-7.32(m, 5H), 6.10(s,1H), 3.91(s, 2H), 1.51-1.58(m, 2H),1.11-1.28(m, 14H), 0.86(t,3H).

Example 7

While several compounds with B-ring structures are shown, other suchcompounds can be prepared to provide a range of X, Y and/or Z moieties,such compounds limited only by commercial synthetic availability of thecorresponding Schiffs base and/or malonate intermediates. Likewise, R₁and R₂ can be varied depending on choice of malonate starting materialor subsequent chemistry on the resulting cannabinoid compound.

Example 8 Receptor Binding Assays

Cell membranes from HEK293 cells transfected with the human CB1 receptorand membranes from CHO-K1 cells transfected with the human CB2 receptorwere prepared. [³H]CP 55,940 having a specific activity of 120 Ci/mmolwas obtained from Perkin-Elmer Life Sciences, Inc. All other chemicalsand reagents were obtained from Sigma-Aldrich. The assays were carriedout in 96 well plates obtained from Millipore, Inc. fitted with glassfiber filters (hydrophilic, GFC filters) having a pore size of 1.2μ. Thefilters were soaked with 0.05% polyethyleneimine solution and washed 5xwith deionized water prior to carrying out the assays. The filtrationswere carried out on a 96 well vacuum manifold (Millipore Inc.), thefilters punched out with a pipette tip directly into scintillation vialsat the end of the experiment, and the vials filled with 5 mlscintillation cocktail Ecolite (+) (Fisher Scientific). Counting wascarried out on a Beckmann Scintillation Counter model LS6500. Drugsolutions were prepared in DMSO and the radioligand was dissolved inethanol.

Incubation buffer: 50 mM TRIS-HCl, 5 mM MgCl₂, 2.5 mM EDTA, 0.5 mg/mlfatty acid free bovine serum albumin, pH 7.4.

Binding protocol for the CB-1 receptor: 8 μg of membranes (20 μl of a1:8 dilution in incubation buffer) was incubated with 5μl of drugsolution (10⁻⁴M to 10⁻¹²M) and 5 μl of 5.4 nM [³H]CP 55,940 in a totalvolume of 200 μl for 90 mins at 30° C. Non-specific binding wasdetermined using 10 μM WIN55,212-2 (K_(i)=4.4 nM). The membranes werefiltered and the filters washed 7× with 0.2 ml ice-cold incubationbuffer and allowed to air dry under vacuum.

Binding protocol for the CB-2 receptor: 15.3 μg of membranes (20 μl of a1:20 dilution in incubation buffer) was incubated with 5 μl of drugsolution (10⁻⁴M to 10⁻¹²M) and 5 μl of 10 nM [³H]CP 55,940 in a totalvolume of 200 μl for 90 minutes at 30° C. Non-specific binding wasdetermined using 10 μM WIN55,212-2 (K_(i)=4.4 nM). The membranes werefiltered and the filters washed 7× with 0.2 ml ice-cold incubationbuffer and allowed to air dry under vacuum.

Data accumulation and statistical analysis: Varying concentrations ofdrug ranging from 10⁻⁴M to 10⁻¹²M were added in triplicate for eachexperiment and the individual molar IC₅₀ values were determined usingGraphPad Prism. The corresponding K_(i) values for each drug weredetermined utilizing the Cheng and Prusoff equation and final data waspresented as K_(i)±S.E.M. of n≧2 experiments.

Functional assays: HEK-293 cell lines stably transfected with a cyclicnucleotide-gated channel and either human CB-1 or CB-2 receptors (BDBiosciences, San Jose, Calif. USA) were seeded in poly-D-lysine coated96-well plates at a density of 70,000 cells per well. Plates wereincubated at 37° C. in 5% CO₂ overnight prior to assay. Plates were thenremoved from the incubator and the complete growth medium (DMEM, 10%FBS, 250 μg/ml G418 and 1 μg/ml puromycin) was replaced with 100 μL DMEMcontaining 0.25% BSA . Next, 100 μL membrane potential dye loadingbuffer (Molecular Devices, Sunnyvale, Calif. USA) was prepared accordingto the manufacturer. The plates were placed back into the incubator for30 minutes and then the baseline fluorescence was read on a BioTekSynergy 2 multi-mode microplate reader (BioTek Instruments, Winooski,Vt. USA) with 540 nm excitation and 590 nm emission filters prior todrug addition. Drugs were added in 50 μL DPBS containing 2.5% DMSO, 1.25μM 5′-(N-ethylcarboxamido)adenosine and 125 μM Ro 20-1724. Plates werethen incubated at room temperature for 25 minutes and fluorescencemeasured again at 540 nm excitation and 590 nm emission.

FIG. 1 depicts the functional activity of compound 5e at the CB-1receptor. FIG. 2 depicts the functional activity of compound 5e at theCB-2 receptor.

Cytoxocity assay: Cells were seeded on a 96 well polystyrene plate infull serum media at a density of 75,000 cells per milliliter, 100 μL perwell. Plates were incubated at 37° C. and 5% CO₂ for 24 hours to allowcell attachment. Drug solutions were prepared in DMSO at 100×concentration and mixed 1:100 in 1% FBS media to yield the desiredconcentration. Drug-media mixtures were vortexed immediately prior toadministration to cells. Full serum media was removed and replaced withdrug-media mixtures and incubated for 18 hours. 10 μL of Cell CountingKit 8 (CCK8, Dojindo #CK04-11) was added to each well to colormetricallyassess viability. After 2-4 hours of incubation with the CCK8 dye,absorbance was read at 450 nm by a BioTek Synergy 2 plate reader.

The cytotoxicity of selected compounds against the glioblastoma braincancer cell line LN-229 is depicted in Table 1. Table 2 shows thecytotoxicity of selected compounds against the glioblastoma brain cancercell line DBTRG05MG.

TABLE 1 Compound EC₅₀ (μM) 5j 52.6 5h 24.6 5k NA 5e 1.6 5n 13.1 5m 41.75b 5.9 5f 71.1 5c 29.2

TABLE 2 Compound EC₅₀ (μM) 5j 55.7 5h 29.2 5k NA 5e 4.1 5n 25.2 5m 56.05b 9.8 5f NA 5c 33.6

Inflammation Studies

Differentiation of Monocytes: To THP-1 human leukemia monocytes (ATCC#TIB-202) in suspension was added phorbol 12-myristate 13-acetate (PMAAldrich #P1585) and ionomycin (Aldrich #I0634), 10 and 500 ng/mlrespectively, to induce differentiation into macrophage-like cells.Cells were seeded at 30,000 cells/well and allowed to incubate at 37° C.in 5% CO₂/95% air for 3-10 days to complete transformation. Media wasrefreshed as needed until assay.

Cytokine Assay: A549 (ATCC #CCL-185), HUV-EC-C (ATCC #CRL-1730), ordifferentiated THP-1 cells were seeded on 96-well polystyrene plates ata density of 300,000 cells/ml (100 μL per well) and incubated at 37° C.in 5% CO₂/95% air for 24 hours to allow cell attachment. Drug solutionswere prepared in DMSO at 100x concentration and mixed 1:100 in 1% FBSmedia to yield the desired concentration.

Plates were then removed from the incubator and the complete growthmedia was replaced with 50 μL media containing 1% FBS andlipopolysaccharide or peptidoglycan at 1 μg/ml (for differentiatedTHP-1), or TNF-α (10 ng/ml) or IL-1β (1 ng/ml) in the case of A549 andHUVEC or without stimulus in the case of control wells. Cells werereturned to the incubator for 1 hour before drug treatments. Drug-mediasolutions were prepared at 2× desired final concentration in mediacontaining 1% FBS and the appropriate stimulus at the previouslymentioned concentration. Control media was also prepared which containedno drug. 50 μL of drug containing media or control was then added toappropriate wells and the plates returned to the incubator for 18 hours.Media supernatants were then removed from the wells and frozen at −80°C. until time of assay.

FIGS. 3-13 depict secretion profiles of various modulators by A549exposed to compound 6b at the EC1 and EC10 in the presence and absenceof TNF-α at 4 and 18 hour intervals. The graph legends are as follows:pyrT 1-4=6b at 8.52 μM for 4 hours; pyrT 2-4=6b at 13.6 μM for 4 hours;pyrT 1-18=6b at 8.52 μM for 18 hours; pyrT 2-18=6b at 13.6 μM for 18hours; TNF=TNF-α at 10 ng/ml.

The invention and the manner and process of making and using it are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as the invention, thefollowing claims conclude this specification.

1. A method of treating a disorder mediated by a cannabinoid receptorcomprising contacting said receptor with a compound in an amount totreat said cannabinoid receptor/mediated disorder, wherein the compoundis of the formula

wherein one of W and V is N and the other is C; X is selected from thegroup consisting of cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, andheterocycloalkylalkyl, wherein the ring portion of each is optionallysubstituted with one, two, three, four or five substituentsindependently selected from the group consisting of halo, alkyl, alkoxy,hydroxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, nitro,alkylamino, dialkylamino, thiol, alkylthiol, haloalkyl, carboxy andalkylcarboxy; Y is selected from the group consisting of S, O, CH₂,CH(CH₃), CH(OH), C(CH₃)(OH), C(CH₃)₂, C(—U(CH₂)_(n)U—), C(O), S(O), andS(O)₂; n is an integer from 1 to 3; U is selected from the groupconsisting of CH₂, S, and O; Z is selected from the group consisting ofH, alkyl optionally substituted with a substituent selected from thegroup consisting of halo, alkyl, alkoxy, hydroxyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, cyano, nitro, amino, alkylamino,dialkylamino, thiol, alkylthiol, haloalkyl, carboxy, alkylcarboxy andcarbamoyl; cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, whereinthe ring portion of each is optionally substituted with one, two, three,four or five substituents independently selected from the groupconsisting of halo, alkyl, alkoxy, hydroxyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, cyano, nitro, amino, alkylamino,dialkylamino, thiol, alkylthiol, haloalkyl, carboxy, alkylcarboxy andcarbamoyl; and R₁ and R₂ are independently selected from the groupconsisting of H and alkyl.
 2. A method according to claim 1 wherein thecannabinoid receptor is selected from CB-1 and CB-2.
 3. A methodaccording to claim 3 wherein the disorder is selected from lung cancer,prostate cancer, colorectal cancer, pancreatic cancer, CNS cancer, braincancer and human glaucoma.
 4. A method according to claim 1 wherein X isselected from the group consisting of_alkyl, phenyl, benzyl, thiopheneand pyridinyl, the ring portion of each is optionally substituted withone to five groups independently selected from the group consisting ofhalo, alkyl and alkoxy; Y is selected from the group consistingof_carbonyl, dimethylmethylene and hydroxymethylene; and Z is selectedfrom the group consisting of alkyl, cycloalkyl, phenyl, and thiophene,each of which is optionally substituted with a substituent selected fromthe group consisting of halo, alkyl, alkoxy, hydroxyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, cyano, nitro, amino, alkylamino,dialkylamino, thiol, alkylthiol, haloalkyl, carboxy, alkylcarboxy andcarbamoyl.
 5. A method according to claim 4 wherein X is alkyl, orbenzyl or phenyl wherein the ring portion is optionally substituted withone, two or three groups independently selected from the groupconsisting of chloro, methyl and methoxy.
 6. A method according to claim5 wherein X is hexyl, benzyl, 3-methoxyphenyl, 3-methylphenyl or3,5-dichlorophenyl.
 7. A compound according to claim 5 wherein Y isdimethylmethylene.
 8. A compound according to claim 5 wherein Z isalkyl, phenyl or cycloalkyl.
 9. A method according to claim 1 whereinthe compound is selected from the group consisting of6-(2-(Thiophen-2-yl)propan-2-yl)-3-m-tolylpyridine-2,4-diol;6-(2-Cyclohexylpropan-2-yl)-3-(3,5-dichlorophenyl)pyridine-2,4-diol;3-(3,5-Dichlorophenyl)-6-(2-phenylpropan-2-yl)pyridine-2,4-diol;3-(3,5-Dichlorophenyl)-6-(2-(thiophen-2-yl)propan-2-yl)pyridine-2,4-diol3-(3,5-dichlorophenyl)-6-(2-methyloctan-2-yl)pyridine-2,4-diol;6-(2-Cyclohexylpropan-2-yl)-3-m-tolylpyridine-2,4-diol;6-(2-Phenylpropan-2-yl)-3-m-tolylpyridine-2,4-diol;2-(2-Methyloctan-2-yl)-5-m-tolylpyrimidine-4,6-diol;6-(2-Methyloctan-2-yl)-3-phenylpyridine-2,4-diol;3-Cyclohexyl-6-(2-methyloctan-2-yl)pyridine-2,4-diol;6′-(2-Methyloctan-2-yl)-2,3′-bipyridine-2′,4′-diol;3-(3-Methoxyphenyl)-6-(2-methyloctan-2-yl)pyridine-2,4-diol; and3-Benzyl-6-(2-methyloctan-2-yl)pyridine-2,4-diol.